Inflammatory Demyelinating Disease Research Articles

Transverse myelitis following bivalent COVID‐19 booster vaccine and quadrivalent seasonal influenza vaccine

Transverse myelitis following bivalent <scp>COVID</scp>‐19 booster vaccine and quadrivalent seasonal influenza vaccine

Diagnostic work-up, findings, and documentation of multiple sclerosis

Although multiple sclerosis is the most common chronic inflammatory demyelinating disease of the central nervous system, the rate of misdiagnosis in clinical practice is high. This is usually due to the inadequate application of the McDonald criteria and misinterpretation of images. This review focuses on typical clinical symptoms, choice of magnetic resonance imaging (MRI) sequences, correct application of the McDonald criteria, and finally interpretation of the images.

The repertoire of CSF antiviral antibodies in patients with neuroinflammatory diseases.

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS). Although various viruses have been proposed to contribute to MS pathology, the etiology of MS remains unknown. Since intrathecal antibody synthesis is well documented in chronic viral infection and neuroinflammatory diseases, we hypothesized whether the patterns of antigen-specific antibody responses associated with various viral exposures may define patients with CNS chronic immune dysregulation. The pan-viral antibody profiling in cerebrospinal fluid (CSF) and serum of patients with MS showed significant differences from those in healthy volunteers and a pattern of antibody responses against multiple viruses, including the previously identified Epstein-Barr virus. These findings demonstrate that virus-specific antibody signatures might be able to reflect disease-associated inflammatory milieu in CSF of subjects with neuroinflammatory diseases.

Validation of elevated levels of interleukin-8 in the cerebrospinal fluid, and discovery of new biomarkers in patients with GBS and CIDP using a proximity extension assay.

Biomarkers for diagnosis of inflammatory neuropathies, assessment of prognosis, and treatment response are lacking. CSF and EDTA plasma from patients with Guillain-Barré syndrome (GBS), chronic inflammatory demyelinating polyneuropathy (CIDP), healthy controls (HC) and disease controls were analyzed with Olink multiplex proximity extension assay (PEA) from two independent cohorts. Levels of interleukin-8 (IL8) were further analyzed with ELISA in patients with GBS, CIDP, paraproteinemia-related demyelinating polyneuropathy (PDN), multifocal motor neuropathy (MMN), HC and disease controls. ROC analysis was performed. Outcome was measured with the GBS-disability score (GBS-ds) or Inflammatory Neuropathy Cause and Treatment (INCAT) score. In CSF, multiplex PEA analysis revealed up-regulation of IL8 in GBS compared to CIDP and HC respectively, and CIDP compared to HC. In addition, levels of IL2RA were upregulated in GBS compared to both HC and CIDP, SELE in GBS compared to HC, and ITGAM, IL6, and NRP1 in GBS compared to CIDP. In plasma, levels of MMP3, THBD and ITGAM were upregulated in CIDP compared to HC. Validation of multiplex IL8 results using ELISA, revealed increased levels of IL8 in CSF in patients with GBS and CIDP versus HC and non-inflammatory polyneuropathies (NIP) respectively, as well as in PDN versus NIP and HC. Levels of IL8 in CSF correlated with impairment in the acute phase of GBS as well as outcome at 6-months follow up. IL8 in CSF is validated as a diagnostic biomarker in GBS and CIDP, and a prognostic biomarker in GBS. Multiplex PEA hereby identifies several potential biomarkers in GBS and CIDP.

Aquaporin 5 in Alzheimer's disease: a link between oral and brain pathology?

Aquaporin 5 in Alzheimer's disease: a link between oral and brain pathology?

The systemic inhibition of the terminal complement system reduces neuroinflammation but does not improve motor function in mouse models of CMT1A with overexpressed PMP22.

Charcot-Marie-Tooth disease type 1A (CMT1A) is the most prevalent hereditary demyelinating neuropathy. This autosomal, dominantly inherited disease is caused by a duplication on chromosome 17p which includes the peripheral myelin protein 22 (PMP22) gene. There is clinical evidence that the disability in CMT1A is to a large extend due to axonal damage rather than demyelination. Over-expression of PMP22 is recently thought to impede cholesterol trafficking causing a total shutdown of local cholesterol and lipid synthesis in the Schwann cells, thus disturbing their ability to remyelinate. But there is a large variety in disease burden between CMT1A patients with the same genetic defect, indicating the presence of modifying factors that affect disease severity. One of these potential factors is the immune system. Several reports have described patients with co-occurrence of CMT1A with chronic inflammatory demyelinating disease or Guillain-Barré syndrome. We have previously shown in multiple animal models that the innate immune system and specifically the terminal complement system is a driver of inflammatory demyelination. To test the contribution of the terminal complement system to neuroinflammation and disease progression in CMT1A, we inhibited systemic complement C6 in two transgenic mouse models for CMT1A, the C3-PMP22 and C3-PMP22 c-JunP0Cre models. Both models over-express human PMP22, and one (C3-PMP22 c-JunP0Cre) also has a Schwann cell-specific knockout of c-Jun, a crucial regulator of myelination controlling autophagy. We found that systemic inhibition of C6 using antisense oligonucleotides affects the neuroinflammation, Rho GTPase and ERK/MAPK signalling pathways in the CMT1A mouse models. The cholesterol synthesis pathway remained unaffected. Analysis of motor function during treatment with C6 antisense oligonucleotides did not reveal any significant improvement in the CMT1A mouse models. This study shows that the contribution of the terminal complement system to progressive loss of motor function in the CMT1A mouse models tested is limited.

Clinical phenotypes of optic nerve damage in patients with neuromyelitis optica spectrum disorder

Neuromyelitis optica spectrum disorders (NMOSD) comprise a group of autoimmune inflammatory demyelinating diseases of the central nervous system that manifest as optic neuritis and transverse myelitis. Its manifestation in the form of optic neuritis makes early diagnosis difficult because neuroimaging of the spinal cord is not a part of the routine examination algorithm for such patients. This article presents the results of a comprehensive ophthalmological examination of 4 patients (8 eyes) diagnosed with NMSOD. Optic neuritis was the disease debut in 3 patients and had 1-2 relapses, in all cases partial optic atrophy with moderate to severe loss of visual function occurred. The clinical picture was characterized by a pronounced heterogeneity in terms of both ophthalmological symptoms, and accession of neurological disorders. Treatment of NMOSD requires differential diagnosis with multiple sclerosis, which depends on the awareness of specialists and the inclusion of antibody titers to aquaporin-4 and myelin oligodendrocyte glycoprotein into the examination algorithm of patients with optical neuritis.

Assessment of Multiple Sclerosis Patients' Knowledge and Behavioral Practice Regarding COVID-19 in Saudi Arabia.

Background Coronavirus disease 2019 (COVID-19) is caused by a coronavirus subtype called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It is crucial to control the spread of coronavirus by understanding the disease and practicing the measures adopted during the COVID-19 pandemic. Multiple sclerosis (MS) is a central nervous system immune-mediated inflammatory demyelinating disease. COVID-19 infection may exacerbate the MS disease and its relapses. Therefore, MS patients are more susceptible to infection because of their immunosuppressive or immunomodulatory medications. Objective We aimed to evaluate the knowledge, attitude, and behaviors of patients with MS in Saudi Arabia regarding the COVID-19 pandemic. Method A quantitative observational cross-sectional study was conducted. MS patients in Saudi Arabia were included in the study population. Data were collected via an online self-reported questionnaire from 214 participants from November 2020 to June 2021. Results A total of 214 MS patients participated in this study. The gender distribution showed that the male participants represented 38.3% (n = 82), while female participants accounted for 61.7% (n = 132).Most MS patients understood the COVID-19 preventive measures. The mean knowledge score was 15.7 (SD = 2.34, range: 1-20), showing an appropriate level of knowledge. While the mean behaviors score was 6.1 (SD = 1.2, range: 2-9), showing good behaviors. The mean score for attitude was 5.4 (SD = 1.77, range: 1-8), showing optimistic attitudes. However, a closer analysis of the participants' answers showed that 74.3% of the patients agreed that the treatment plan should be discussed with their doctors during the pandemic. In addition, almost half of the participants (49.1%) agreed that being an MS patient means they are at higher risk of getting infected by the virus. Data also showed that 17% of patients continued to attend social events involving many people. Also, 28.0% of the patients reported being in crowded places. Conclusion MS patients' risk of COVID-19 might be linked to their knowledge, attitude, and behaviors. Our results suggest that although MS patients have a high knowledge and good attitude and behaviors, it is still essential to have health education programs among MS patients to reduce the risk of SARS-CoV-2 infection and the impact of the COVID-19 pandemic on MS patients' care. Knowledge, attitude, and behaviors toward the COVID-19 pandemic can highlight the importance of education programs and translate the findings into action to minimize the disease risk.

PiRNA and miRNA Can Suppress the Expression of Multiple Sclerosis Candidate Genes

Multiple sclerosis (MS) is a common inflammatory demyelinating disease with a high mortality rate. MS is caused by many candidate genes whose specific involvement has yet to be established. The aim of our study was to identify endogenous miRNAs and piRNAs involved in the regulation of MS candidate gene expression using bioinformatic methods. A program was used to quantify the interaction of miRNA and piRNA nucleotides with mRNA of the target genes. We used 7310 miRNAs from three databases and 40,000 piRNAs. The mRNAs of the candidate genes revealed miRNA binding sites (BSs), which were located separately or formed clusters of BSs with overlapping nucleotide sequences. The miRNAs from the studied databases were generally bound to mRNAs in different combinations, but miRNAs from only one database were bound to the mRNAs of some genes. For the first time, a direct interaction between the complete sequence of piRNA nucleotides and the nucleotides of their mRNA BSs of target genes was shown. One to several clusters of BSs of miRNA and piRNA were identified in the mRNA of ADAM17, AHI1, CD226, EOMES, EVI5, IL12B, IL2RA, KIF21B, MGAT5, MLANA, SOX8, TNFRSF1A, and ZBTB46 MS candidate genes. These piRNAs form the expression regulation system of the MS candidate genes to coordinate the synthesis of their proteins. Based on these findings, associations of miRNAs, piRNAs, and candidate genes for MS diagnosis are recommended.

Neurofilament light chains in serum as biomarkers of axonal damage in early MS lesions: a histological–serological correlative study

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease associated with axonal injury, and neurofilament light chains in serum (sNfL) are considered a biomarker for this damage. We aimed to investigate the relationship between sNfL and the axonal damage in early MS lesions in a special cohort of biopsied patients. sNfL from 106 biopsied patients with 26 follow-up samples were analyzed using single-molecule array (SiMoA) technology. Findings were correlated with clinical parameters and histological findings of acute axonal damage (APP-positive spheroids) and axonal loss in different lesion stages. A median of 59 pg/ml sNfL was found (range 8–3101 pg/ml). sNfL levels correlated with APP-positive spheroids in early active demyelinating lesions that represent the earliest lesion stages (p < 0.01). A significant negative correlation between sNfL levels in follow-up blood samples and axonal density in normal-appearing white matter was also observed (p = 0.02). sNfL levels correlated with the Expanded Disability Status Score at biopsy (p < 0.01, r = 0.49) and at last clinical follow-up (p < 0.01, r = 0.66). In conclusion, sNfL likely represent a compound measure of recent and ongoing neuroaxonal damage. We found that sNfL in biopsied MS patients correlate with acute axonal damage in the earliest MS lesion stages. Determination of sNfL levels thus allows insight into brain pathology and underlines the relevance of relapse-associated lesional pathology. Axonal loss in normal-appearing white matter contributes to sNfL levels independent of relapses. Since sNfL levels correlate with clinical disability, they may predict the future disability of patients and help with individual treatment decisions.

Granzyme B in circulating CD8+ T cells as a biomarker of immunotherapy effectiveness and disability in neuromyelitis optica spectrum disorders.

Neuromyelitis optica spectrum disorders (NMOSD) are chronical inflammatory demyelinating diseases of the central nervous system (CNS) and the underlying mechanism remains unclear. Several recent studies have demonstrated that T cells play a pivotal role in the pathogenesis of NMOSD.In this study, we investigated CD8+ T cell phenotypes and levels of the cytotoxic protein granzyme B (GzmB), as well as their potential clinical application in NMOSD. In this study, 90 peripheral blood samples were collected from 59 NMOSD patients with seropositive anti-aquaporin-4 (AQP4) antibodies and 31 sex- and age-matched healthy donors (HDs). Flow cytometry was used to detect circulating levels of GzmB and CD8+ T cell subpopulations, including naïve (TN, CCD7+CD45RA+), central memory (TCM, CCD7+CD45RA-), effector memory (TEM, CCD7-CD45RA-), terminal differentiation effector memory cells (TEMRA, CCD7-CD45RA+) in both groups. The associations between GzmB levels in CD8+T cells and clinical characteristics of NMOSD were evaluated. NMOSD patients exhibited significantly decreased proportions of CD8+TN cells and increased proportions of highly differentiated CD8+T cells (TEMRA) compared with HDs. In addition, levels of GzmB in CD8+ T cells were markedly higher in NMOSD patients than in HDs. Moreover, we observed that high proportions of GzmB-expressing CD8+ T cells were more common in patients with a poor response to immunotherapies, and showed a good potential to distinguish poor responders from responders (ACU=0.89). Clinical correlation analysis indicated that high levels of GzmB in CD8+ T cells were not only related to severe disability but also significantly associated with increased serum levels of neurofilament light (NFL) and glial fibrillary acidic protein (GFAP). Multivariate linear regression analyses further suggested that GzmB expression in CD8+ T cells was predominantly associated with disability and immunotherapy effectiveness in NMOSD, independent of the sex, age, and disease phase. Transcription factor T-bet in CD8+ T cells were also significantly elevated in NMOSD and were associated with increasing number of circulating CD8+TEMRA cells and GzmB-expressing CD8+T cells. Our study support the involvement of GzmB-expressing CD8+ T cells in the inflammatory response in patients with NMOSD and provide a potential biomarker for disease immunotherapy effectiveness and disability progression.

Anti-IL-6 therapies in central nervous system inflammatory demyelinating diseases.

Current treatments for central nervous system (CNS) inflammatory demyelinating diseases (IDDs) include corticosteroids, plasma exchange, intravenous immunoglobulin, and immunosuppressant drugs. However, some patients do not respond well to traditional therapies. In recent years, novel drugs, such as monoclonal antibodies, targeting the complement component C5, CD19 on B cells, and the interleukin-6 (IL-6) receptor, have been used for the treatment of patients with refractory CNS IDDs. Among these, tocilizumab and satralizumab, humanized monoclonal antibodies against the IL-6 receptor, have shown beneficial effects in the treatment of this group of diseases. In this review, we summarize current research progress and prospects relating to anti-IL-6 therapies in CNS IDDs.

Correlation of IgH-CDR3 Immune Repertoire Diversity Test in Peripheral Blood of Neuromyelitis Spectrum Diseases.

Neuroretinitis spectrum disorder (NMOSD) is generally regarded as an acute or subacute inflammatory demyelinating disease of the central nervous system, mainly involving the optic nerve and spinal cord, mediated by humoral immunity. To address these questions, this work established an immunomic library of the heavy chain complementarity determinant 3 (gHI-CDR3) of peripheral blood lymphocyte B cell receptors. The library was established in patients with a spectrum of neurosyphilis-retinitis disorders. Six NMOSD patients and six healthy volunteers were recruited, and the NMOSD group was divided into an early-onset group and a stable group according to treatment conditions. The IgH-CDR3 gene fragment cultured in vitro was amplified by multiplex PCR technology, and the gene was sequenced by the second-generation high-throughput sequencing technology, and the statistical analysis was carried out by the method without reference. The quantity, type, and diversity of IgH-CDR3 in peripheral blood B lymphocytes of NMOSD patients were significantly lower than those of normal group (P > 0.05); the variation of IgH-CDR3 sequence in the initial stage of treatment was higher than that in the stable stage (P > 0.05); the replication frequency of the characteristic gene “CASSICLGSGCGGYYYGMDVW” was significantly increased in patients at the initial stage of NMOSD treatment (P < 0.05). The conclusion was that the gene expression and gene expression analysis of NMOSD patients could accurately judge the condition of NMOSD patients, evaluate their efficacy, and provide new molecular targets and new theoretical basis for clinical application.

How to make a decision on the choice of therapy for multiple sclerosis with sarcoidosis comorbidity?

M ultiple sclerosis (MS) is a chronic inflammatory demyelinating disease. The diagnosis is made on the basis of McDonald’s diagnostic criteria, which include clinical manifestations, characteristic lesions registered by magnetic resonance imaging (MRI) and analysis of cerebrospinal fluid, which

Transcriptional abnormalities in induced pluripotent stem cell-derived oligodendrocytes of individuals with primary progressive multiple sclerosis

Multiple sclerosis (MS) is the most common neurological disorder in young adults and is classically defined as a chronic inflammatory demyelinating disease of the central nervous system (CNS). Although MS affects millions of people worldwide, its underlying cause remains unknown making discovery of effective treatments challenging. Whether intrinsic or extrinsic factors contribute to MS initiation and progression is still unclear. This is especially true for primary progressive MS (PPMS), the rarest form of the disease, in which progressive and irreversible loss of neurological function is often observed in the absence of an overt immune-inflammatory response. To test the hypothesis that intrinsic dysfunction in oligodendrocytes (OLs), the primary targets of damage in MS, may contribute to PPMS etiopathology, we differentiated human induced pluripotent stem cell (hiPSC) lines derived from PPMS and healthy individuals into mature OLs to compare their transcriptional profile. PPMS derived OLs displayed hundreds of differentially expressed genes compared to control OLs, many associated with cell adhesion, apoptosis and inflammation, including the inflammasome component Nlrp2, which was highly upregulated. NLRP2 immunoreactivity in OLs was confirmed in post-mortem PPMS brain tissues, with higher expression than in control tissues. Altogether, our findings suggest that mature OLs in PPMS affected individuals carry intrinsic abnormalities that could contribute, at least in part, to the pathophysiology of this form of the disease.

Author Response: Teaching NeuroImage: Leber Hereditary Optic Neuropathy With Longitudinal Spinal Cord Lesion Mimicking Spinal Cord Infarction.

We are thankful for the interest and comments on our case report.1 Indeed, the longitudinally transverse myelopathy and the history of optic neuropathy in the present case might lead to a clinical suspicion of neuromyelitis optic spectrum disorders (NMOSDs) or other inflammatory demyelinating diseases. Although the negative serum AQP4-IgG and MOG-IgG antibodies could not deny the diagnosis of NMO/NMOSD, the large maternally inherited pedigree of genetically confirmed optic neuropathy highly suggested a multiorgan-involved mitochondrial disease rather than a coincidence of 2 separate diseases (LHON and NMOSD).2 Zalewski et al.3 reported that a significant MRI enhancement of the anterior gray matter was not uncommon and could even be observed in 39% of spinal cord infarctions.

Epidemiological study of multiple sclerosis in the Illawarra region.

Multiple sclerosis (MS) is an autoimmune inflammatory demyelinating disease that causes significant disabilities. Latest MS epidemiological data in Australia reveal rising prevalence. No epidemiological study of MS has been conducted so far in the Illawarra region. To calculate prevalence and incidence of MS in the Illawarra region and compare with data from other regions, states and the national prevalence. Data of MS patients in the Illawarra region were collected from hospital medical records, ambulatory care units and hospital pharmacy. Prevalence was calculated for alive MS patients on 30 June 2018 expressed per 100 000 population. Yearly adjusted incidence rate was calculated for 10 years (2009-2019), expressed as cases per 100 000 population-years. Estimated MS prevalence in the Illawarra region was 116.6 per 100 000 population with yearly incidence (2009-2019) of 5.06 cases per 100 000 population-years (female to male, 3:1). Relapsing-remitting MS (RRMS) was the most common type (277/397; 69.7%) with primary progressive MS (PPMS) in 52/397 (13%), and secondary progressive MS (SPMS) in 45/397 (11.3%; unknown in 23). The commonest age at diagnosis ranged between 30 and 39 years for all types with RRMS and PPMS between 30-39 years and 40-49 years respectively. The most common recorded treatment was natalizumab (103 patients), followed by fingolimod (82 patients) and interferon (58 patients). The calculated MS prevalence in the Illawarra region is higher than New South Wales and the Australian average MS prevalence. Further epidemiological studies focussing on MS risk factors and other factors bearing on MS prevalence in the Illawarra region are required.

Onset of various CNS inflammatory demyelination diseases following COVID-19 vaccinations

BackgroundSince the start of COVID-19 vaccination worldwide, there have been several reports of inflammatory demyelinating diseases of the central nervous system (CNS-IDDs) following vaccination. MethodsWe prospectively collected cases of new-onset CNS-IDDs with a temporal relationship between disease onset and COVID-19 vaccination and investigated their proportion among newly registered cases of CNS-IDD over the past year. ResultsAmong 117 cases, 10 (8.5%) had their first disease manifestation within one month following COVID-19 vaccination: 2 multiple sclerosis, 2 neuromyelitis optica spectrum disorder, 3 MOG antibody-associated disease, and 3 unclassified CNS-IDDs. ConclusionThis observation suggests that COVID-19 vaccination may trigger the onset of various CNS-IDDs in susceptible individuals.

Results of a study of the quality of life in patients with highly active multiple sclerosis in Russia

Multiple sclerosis (MS) is a chronic autoimmune inflammatory demyelinating and neurodegenerative disease of the central nervous system. Now 2.8 million people in the world suffer from MS, since 2000 every 5 years there has been an increase in the number of MS patients by 10%. At the same time, the number of cases with highly active MS (HAMS) is increasing, i.e. cases of MS with two or more exacerbations without taking specific pathogenetic therapy or one exacerbation during taking MS disease-modifying therapies (DMTsMS), which is accompanied by the corresponding MRI data of the brain and spinal cord (presence of new or active lesions). Previously, there were no studies of quality of life (QoL) in this subgroup of patients in the world.Objective: to compare the QoL indicators of patients with HAMS with those of healthy people and patients with a typical course of relapsingremitting MS (RRMS).Patients and methods. The study included data on 518 patients from 14 regions of the Russian Federation for 2020–2021 years, in whom HAMS was confirmed during a second examination. We used the results of the analysis of clinical data from neurologists and data from questionnaires filled out by patients with HAMS. Two questionnaires were used in the work – the general (non-specific) Questionnaire for assessing the QoL, SF-36 (The MOS 36-item Short-Form Health Survey) and a special questionnaire for MS patients – MusiQoL (Multiple sclerosis Quality of Life).Results and discussion. Almost all indicators of QoL in HAMS were below the control. When compared with the typical course of RRMS, a more pronounced decrease in daily activity indicators, a significant impact of clinical symptoms on QoL, a negative attitude of patients towards the healthcare system, and a low overall health index were noted. Pearson correlation analysis revealed a stronger effect on QoL parameters of the frequency of exacerbations in HAMS than in RRMS.Conclusion. The data obtained in the study indicate the need for more active management of patients with HAMS using second-line DMTsMS.

Visualizing Sphingosine-1-Phosphate Receptor 1(S1P1) Signaling During Central Nervous System De- and Remyelination.

Multiple sclerosis (MS) is an inflammatory-demyelinating disease of the central nervous system (CNS) mediated by aberrant auto-reactive immune responses. The current immune-modulatory therapies are unable to protect and repair immune-mediated neural tissue damage. One of the therapeutic targets in MS is the sphingosine-1-phosphate (S1P) pathway which signals via sphingosine-1-phosphate receptors 1-5 (S1P1-5). S1P receptors are expressed predominantly on immune and CNS cells. Considering the potential neuroprotective properties of S1P signaling, we utilized S1P1-GFP (Green fluorescent protein) reporter mice in the cuprizone-induced demyelination model to investigate in vivo S1P - S1P1 signaling in the CNS. We observed S1P1 signaling in a subset of neural stem cells in the subventricular zone (SVZ) during demyelination. During remyelination, S1P1 signaling is expressed in oligodendrocyte progenitor cells in the SVZ and mature oligodendrocytes in the medial corpus callosum (MCC). In the cuprizone model, we did not observe S1P1 signaling in neurons and astrocytes. We also observed β-arrestin-dependent S1P1 signaling in lymphocytes during demyelination and CNS inflammation. Our findings reveal β-arrestin-dependent S1P1 signaling in oligodendrocyte lineage cells implying a role of S1P1 signaling in remyelination.